Purine Quadruplexes Stabilised by a Modified Porphyrin Analogue have Implications for mRNA Viral Replication

Abstract

Simon Chapman

Recent research has clearly demonstrated that suppression of replication in mRNA viruses may be possible by stabilising viral guanine quadruplexes (G4s). Whilst it has been previously only proposed that G4s could fold in the SARS- CoV 2 genome, research confirming their definitive presence has since been published. A suggestion was made that polyadenylation of SARS-CoV 2 might allow adenine quadruplexes (A4s) to fold as the necessary sequence was available. The quadruplex topology appeared relatively stable. This further implies that there is potential for purine quadruplexes to compromise the viral replication mechanism by improved stability. A4s in this scenario could compromise effective functions in the poly(A) tail. However, whilst telomestatin and pyridostatin stabilise G4s, both are large molecules and are not approved in general use. Furthermore, both have poor solubility and bioavailability. Moreover, both have been trialled in G4 research with inconclusive outcomes. This current project designed and assessed a smaller, porphyrinoid tetra-thionated analogue, PTTA, derived from an oxidised norcorrole as a possible acceptable alternative. Molecular dynamics, ADMET and pharmacokinetic data were compared with results for telomestatin, pyridostatin and porphyrin. By these metrics and comparators, PTTA is characterised by enhanced stabilisation of purine quadruplexes and with a pharmacokinetic potential to reduce cytotoxicity.

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